MX2010010869A

MX2010010869A - Preventive and/or remedy for vascular diseases.

Info

Publication number: MX2010010869A
Application number: MX2010010869A
Authority: MX
Inventors: Tomihisa Kawasaki; Toshiyuki Funatsu; Chinatsu Sakurai
Original assignee: Astellas Pharma Inc
Priority date: 2008-04-01
Filing date: 2009-03-31
Publication date: 2010-11-12
Also published as: ZA201006660B; JPWO2009123210A1; EP2258364A1; WO2009123210A1; EP2258364A4; IL208231A0; KR20100137448A; BRPI0908584A2; JP5589838B2; CA2720278A1; US20110034504A1; RU2010144554A; AU2009232710A1; CN101983056A

Abstract

Provided is an excellent medicinal composition for preventing and/or treating vascular diseases. A medicinal composition for preventing and/or treating vascular diseases which comprises: 1) a COX-1 selective inhibitor; and 2) clopidogrel or a pharmaceutically acceptable salt thereof. The medicinal composition for preventing and/or treating vascular diseases thus provided is particularly useful as a medicinal composition for preventing and/or treating arterial thrombosis, ischemic heart disease, ischemic brain disease, pulmonary embolism, peripheral circulation disorder, restenosis and reocclusion, essential thrombocytosis and so on.

Description

AGENT TO PREVEN GO AND / OR TREAT IN FERME DADES VASC U LARES Field of the invention This invention relates to an agent for preventing and / or treating vascular diseases, characterized in that a selective COX-1 inhibitor or a pharmaceutically acceptable salt thereof is combined with clopidogrel or a pharmaceutically acceptable salt thereof.

Background of the I nvention Since its discovery by Donne in 1 942 (C. R. Acad. Sci. (Paris), 1 4, 336-68, 1 842), platelets have long been treated as a blood component that is necessary for hemostasis. In these days, it has been revealed that the platelet not only simply plays the major role of the mechanism of hemostasis but also shows multifunctional properties such as clinically significant arteriosclerosis formation, circulatory organ diseases including thrombotic diseases, cancer metastasis, inflammation, rejection reaction after transplant and participation in immune reaction.

In recent years, PTCA therapy and method of stent placement have spread rapidly and obtained certain results in the treatment of aortic diseases based on stenosis and coronary stenosis such as angina pectoris, myocardial infarction and the like. However, these 4 Therapeutic methods damage blood vessel tissues including endothelial cells, thus posing a problem that causes acute coronary obstruction and, in addition, restenosis that occurs in the chronic stage. The platelet plays an important role in several thrombotic events after such revascularization therapies (Catheter Cardiovasc, Interv., 69: 637-42, 2007). Accordingly, the efficacy of an antiplatelet agent is desired, but the sufficient effect by conventional antiplatelet agents has not yet been proven.

Under such circumstances, antiplatelet agents such as aspirin, cilostazol, prostaglandin 12, prostaglandin E, ticlopidine, clopidogrel (Patent References 2 and 3), dipyridamole and the like have been used as preventive or therapeutic agents for these diseases of the circulatory system. Among these drugs, aspirin and clopidogrel are now generally used alone or concomitantly, with the purpose of carrying out secondary prevention of the thrombotic event of patients with thromboembolism.

Although clopidogrel significantly reduced the event-occurrence ratio by a factor of 8.7% based on aspirin (clopidogrel 5.83% / year versus aspirin 5.32% / year) in a CAPRIE trial performed using patients with thromboembolism as subjects, the difference is not considerable (reference not patentable 1), so that a demand has been directed towards the aspect of a drug that shows an index of inhibition of major event.

On the one hand, a result of the meta-analysis has been reported on the inhibition rate of aspirin event, which was of 1 9% by its administration from 500 to 1 500 mg, 26% by its administration from 1 60 to 325 mg, 32% by its administration from 75 to 1 50 mg and 1 3% by 75 mg or less, so that clear dose dependence was not found (Br. J. Med. "324: 71-86, 2002) In addition, a meta-analysis result has also been reported with respect to gastrointestinal bleeding as a side effect of aspiration, but the dose dependence was not found in its frequency of expression and the frequency was 2 to 3% ( Br. J. Med., 321: 1 1 83-7, 2000) According to these analytical results, a low dose of aspirin has been recommended when preventing the thrombotic event is the object, but in particular, it has been reported that the rate of inhibition of the event for high risk patients was low, that is, approximate 25% (N. Engl. J. Med. , 353: 2373-83, 2005).

As described above, the rate of inhibition of the aspirin and clopidogrel event is not satisfactory, and is considered to be insufficient particularly for patients at high risk of acute coronary syndrome (ACS because of their signs in i ng ls) and the like. According to the previous one, the effect of using combination of clopidogrel in aspirin in a CU RE trial in patients with increased ACS without ST as the objects has been examined. According to this, the event index was reduced significantly by a factor of 20% in the combination use group, compared to the aspirin alone group (Nofpatentable Reference 2). In addition, an effect of inhibition of the significant secondary thrombotic event has been reported at the time of the use of combination of aspirin and clopidogrel for patients with ischemic diseases, also by a CHARISMA trial (Reference not patentable 3). However, it has been reported that hemorrhagic side effects were significantly increased in the combination use group by the CURE trial, and the utility of the combination group was not found with respect to the primary prevention effect of low risk patients. the CHARISMA essay. Therefore, as the directionality of future antithrombotic therapy, in addition to the creation of a drug capable of achieving a high rate of inhibition of the additional event, it is considered that a multidisciplinary therapy of the use of combination of superior drugs may be inaccurate with the consideration not only strength of the effect of the drug but also of hemorrhagic side effects and the accomplishment of the adjustment of the appropriate use and dose of such drugs.

Aspirin is an irreversible inhibitor of an enzyme that limits the metabolic path of arachidonic acid, cyclooxygenase-1 (COX-1). COX has subtypes and in addition to the constitutive type COX-1, an inducible COX-2 type is known that is expressed at the time of inflammation. Agree with the last review, it has been reported that the production of thromboxane A2 (TXA2) whose cause has strong platelet aggregation activity and vasoconstrictor activity originate from the COX-1 platelet, and on the one hand, the production of prostacyclin (PG I2). ) which causes strong platelet aggregation inhibitory activity and vasodilator activity originates mainly from vascular endothelial COX-2 and in part from COX-1 (J. Clin.Invest., 1 1 6: 4-1 5, 2006). In addition, there is a study report that gastric ulcer caused by aspirin and NSAIDs is caused by inhibiting COX-1 and COX-2 (Gastroenterology, 1 1 9: 796 - 14, 2000).

On the one hand, it is known that selective COX-1 inhibitors do not generate the gastrointestinal side effects that have been found in conventional NSAIs Ds (Patent Reference 1). However, there are no reports indicating that these compounds improve the antithrombotic action of other antithrombotic agents and gastrointestinal disorders and similar side effects are not generated by their concomitant use with other antithrombotic agents.

Patent Reference 1: International Publication No. WO 03/0401 1 0 Patent Reference 2 patent: North American Patent Specification No. 4,529,596.

Patent Reference 3: US Patent Specification No. 4,847, 265.

Reference of No-patent 1: Lancet 348: 1 329-99, 1 996 Non-patentable reference 2: Am. Heart J. , 1 45: 595-601, 2003 Non-patentable reference 3: N. Eng. J. Med. , 354: 1 706-1 7, 2006 Brief Description of I nven tio n Problems that the Ionvention will solve An object of the present invention is to provide an excellent pharmaceutical composition for preventing and / or treating vascular diseases, which shows improved efficacy and few side effects compared to aspirin, clopidogrel and similar drugs marketed for vascular diseases and their combination of use in therapy .

Means to solve problems The present inventors have confirmed that when "a COX-1 selective inhibitor or a pharmaceutically acceptable salt thereof" (for example, 3-methoxy-1,5-bis (4-methoxyphenyl) -1 H-1, 2, 4- triazole (Compound A, below)) and an antithrombotic agent having a different mechanism of action, concomitantly (+) - (S) -2- (2-chlorophenyl) -2- (4,5,6,7- methyl tetrahydrothieno [3,2-c] pyridin-5-yl) acetate (clopidogrel, below) or a pharmaceutically acceptable salt thereof, shows a remarkably excellent effect in preventing and / or treating vascular diseases and more addicionally, side effects such as gastrointestinal disorders and the like are not generated, as compared to a case of administering Compound A or clopidogrel alone and a case of concomitant use of aspirin and clopidogrel, and thereby have achieved the present invention.

It is an object of the present invention to provide an agent for preventing and / or treating vascular diseases, characterized in that a selective COX-1 inhibitor or a pharmaceutically acceptable salt thereof is combined with clopidogrel or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a pharmaceutical composition, comprising 1) a selective COX-1 inhibitor or a pharmaceutically acceptable salt thereof and 2) clopidogrel or a pharmaceutically acceptable salt thereof.

A further object of the present invention is to provide a pharmaceutical composition for preventing and / or treating vascular diseases, comprising 1) a COX-1 selective inhibitor or a pharmaceutically acceptable salt thereof and 2) clopidogrel or a pharmaceutically acceptable salt thereof. same.

A further object of the present invention is to provide the use of a selective COX-1 inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing and / or treating vascular diseases in combination with clopidogrel or a pharmaceutically acceptable salt thereof. same.

A further object of the present invention is to provide a method for preventing and / or treating vascular diseases, comprising administering 1) an effective amount of clopidogrel or a pharmaceutically acceptable salt thereof and 2) an effective amount of a selective COX-1 inhibitor. or a pharmaceutically acceptable salt thereof to a human or animal previously mentioned.

A further object of the present invention is to provide a process for producing a pharmaceutical composition for preventing and / or treating vascular diseases, comprising the mixture 1) of a COX-1 selective inhibitor or a pharmaceutically acceptable salt thereof, and 2) clopidogrel or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

A further object of the present invention is to provide a pharmaceutical composition for preventing and / or treating vascular diseases, comprising 1) a formulation comprising a selective COX-1 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient and 2) an insert of package indicating that the formulation is used in combination with a formulation containing clopidogrel or a pharmaceutically acceptable salt thereof as an active ingredient.

Effect of the Invention The present invention is useful for providing a pharmaceutical composition for preventing and / or treating vascular diseases. In addition, the present invention is particularly useful for providing a pharmaceutical composition for preventing and / or treating the aforementioned diseases, in which side effects such as gastrointestinal disorders and the like are reduced.

Brief Description of the Drawings Fig. 1 shows the amount of thrombi in a model of indium thrombus with iron rabbit chloride of I ndias, in the case of administering Compound A, aspirin or clopidogrel only, in the case of concomitantly administering Compound A or aspirin with clopidogrel or in the case of administering the vehicle only. P-con vertical axis represents the total thrombus protein. On the horizontal axis, C represents a vehicle administration group (control), and CLO 1 represents a group of administration of 1 mg / kg of clopidogrel, Compound A3 represents a group of administration of 3 mg / kg of Compound A , Compound A3 + CLO 1 represents a concomitant group of administration of 3 mg / kg of Compound A and 1 mg / kg of clopidogrel, ASA 300 represents a group of administration of 300 mg / kg of aspirin, and ASA 300 + CLO 1 represents a concomitant group of administration of 300 mg / kg of aspirin and 1 mg / kg of clopidogrel, respectively. The * in the table indicates that it is a group that has a significant difference with a critical speed of less than 5%, as a result of the Student's t-test. The ** in the table indicate that it is a group that has a significant difference with a critical speed of less than 1%, as a result of the Student's t-test. The number (n) in parentheses represents the number of rabbit animals of I ndias in each group.

Fig. 2 shows the lesion length of the gastric mucosa in the case of administering compound A, aspirin or clopidogrel only to normal guinea pigs. U »l (mm) of the vertical axis represents the sum total of lesion lengths found on the surface of the gastric mucosa, and the result is plotted for each individually. In addition, the horizontal line in the drawing represents the average value of each group. On the horizontal axis, C represents a vehicle administration group (control), and CLO 1 represents a group of administration of 1 mg / kg of clopidogrel, Compound A 100 represents a group of administration of 100 mg / kg of Compound A , ASA 300 represents a group of administration of 300 mg / kg of aspirin, and CLO 100 represents a group of administration of 100 mg / kg of clopidogrel, respectively. The ** in the figure indicate that it is a group that has a significant difference with a critical velocity of less than 1%, as a result of the Wilcoxon thick sum test.

Fig. 3 shows the lesion length of the gastric mucosa in the case concomitantly administering Compound A or aspirin together with clopidogrel to normal guinea pigs. U «l (mm) of the vertical axis represents the sum total of lengths of lesions found on the surface of the gastric mucosa, and the result is diagrammed for each one individually. In addition, the horizontal line in the drawing represents the average value of each group. On the horizontal axis, C represents a concomitant vehicle administration group and 3 mg / kg of clopidogrel, and Compound A 100 represents a concomitant administration group of 100 mg / kg of Compound A and 3 mg / kg of clopidogrel, and ASA 300 represents a concomitant administration group of 300 mg / kg aspirin and 3 mg / kg clopidogrel, respectively. The ** in the figure indicate that it is a group that has a significant difference with a critical velocity of less than 1%, as a Wilcoxon thick sum test result.

Fig. 4 is a graph showing the inhibition ratio of TXB2 production induced by aggregation using rabbit guinea pig whole blood when Compound A or aspirin was administered concomitantly with clopidogrel. On the horizontal axis, C represents a vehicle administration group (control), and Compound A represents a concomitant administration group of 3 mg / kg of Compound A and 1 mg / kg of clopidogrel, and ASA represents a group of administration concomitant of 300 mg / kg of aspirin and 1 mg / kg of clopidogrel, respectively. ? (%) of the vertical axis represents the inhibition ratio when the vehicle administration group was considered as 0% inhibition ratio. The ** in the table indicate that it is a group that has a significant difference with a critical velocity of less than 1%, as a result of the Student's t-test. The number in parentheses represents the number of guinea pig animals in each group.

Fig. 5 is a graph showing the inhibition ratio of PGE2 production induced by LPS using rabbit guinea pig whole blood when Compound A or concomitant aspirin was administered with clopidogrel. On the horizontal axis, C represents a vehicle administration (control) group, and Compound A represents a concomitant administration group of 3 mg / kg of Compound A and 1 mg / kg of clopidogrel, and ASA represents a concomitant administration group of 300 mg / kg of aspirin and 1 mg / kg of clopidogrel, respectively. ? (%) of the vertical axis represents the inhibition ratio when the vehicle administration group was considered as the 0% inhibition ratio. The ** in the table indicate that it is a group that has a significant difference with a critical speed of less than 1%, as a result of the Student's t-test. The number in parentheses represents the number of guinea pig animals in each group.

Best Way to Carry Out the Invention The following shows the preferred embodiments of the present invention. (1) An agent for preventing and / or treating vascular diseases, characterized in that Compound A or a pharmaceutically acceptable salt thereof is combined with clopidogrel or a pharmaceutically acceptable salt thereof. (2) An agent for preventing and / or treating arterial thrombosis, ischemic heart disease [e.g., angina pectoris (e.g., stable angina pectoris, unstable angina pectoris including impending infarction, and the like), myocardial infarction (by example, acute myocardial infarction and the like), coronary thrombosis and the like], cerebral ischemic disease [e.g. cerebral infarction (e.g., acute cerebral thrombosis and the like), cerebral thrombosis (e.g., cerebral embolism and the like), transient cerebral ischemia (e.g., transient ischemic attack and the like) and the like], pulmonary embolism, peripheral circulation disorder [ for example, thromboangiitis obliterans (ie, Buerger's disease), Raynaud's disease and the like], restenosis, and reocclusion [eg, restenosis and / or reocclusion after percutaneous transluminal coronary angioplasty (PTCA for its sigl es in i ng lés), restenosis and reocclusion after administration of a thrombolytic agent (e.g., plasminogen tissue activating factor (tPA for its English acronym) or the like)] or essential thrombocytosis, characterized in that Compound A or a pharmaceutically salt acceptable thereof is combined with clopidogrel or a pharmaceutically acceptable salt thereof. (3) An agent for preventing and / or treating arterial thrombosis, ischemic cardiac disease [e.g., angina pectoris (e.g., stable angina pectoris, unstable angina pectoris including impending infarction, and the like), myocardial infarction ( for example, acute myocardial infarction and the like), coronary thrombosis and the like], cerebral ischemic disease [e.g., cerebral infarction (e.g., acute cerebral thrombosis and the like), cerebral thrombosis (e.g., cerebral embolism and the like), ischemia transient cerebral (eg, transient ischemic attack and the like) and the like] or restenosis and reocclusion [by example, restenosis and / or reocclusion after percutaneous transluminal coronary angioplasty (PTCA), restenosis and reocclusion after administration of a thrombolytic agent (e.g., plasminogen tissue activating factor (tPA) or the like)], characterized in that Compound A or a pharmaceutically acceptable salt thereof is combined with clopidogrel or a pharmaceutically acceptable salt thereof.

The following illustratively describes suitable examples of various definitions included in the scope of the present invention, described in the foregoing and followed by this specification.

Compound A to be used in the present invention is a compound represented by the following structural formula (I).

[Chemical product 1] The clopidogrel to be used in the present invention is a compound represented by the following structural formula (I I).

[Chemical product 2] (II) "Vascular disease" means a disease or a symptom caused by thrombi in the blood vessel. Illustratively, it includes arterial thrombosis, ischemic cardiac disease [e.g., angina pectoris (e.g., stable angina pectoris, unstable angina pectoris including impending infarction, and the like), myocardial infarction (e.g., acute myocardial infarction and similar), coronary thrombosis and the like], ischemic cerebral disease [e.g., cerebral infarction (e.g., acute cerebral thrombosis and the like), cerebral thrombosis (e.g., cerebral embolism and the like), transient cerebral ischemia (e.g., ischemic attack) transitory and similar) and similar], pulmonary embolism, peripheral circulation disorder [e.g. thromboangiitis obliterans (ie Buerger's disease), Raynaud's disease and the like], restenosis and reocclusion [e.g., restenosis and / or restenosis and / or reocclusion after transluminal coronary angioplasty] percutaneous (PTCA), restenosis and reocclusion after administration of an ithic thrombolytic agent (e.g., tissue activation factor of plasminogen (tPA) or the like)], essential thrombocytosis and the like, but not limited thereto.

According to this specification, "the selective inhibitor COX-1" means a substance having a property in which its inhibitory activity for COX-1 is stronger than its inhibitory activity for COX-2. Preferably, it means "a compound having an inhibition ratio of B2 production of thromboxane induced by aggregation of 70% or more based on the group of vehicle and also that it has an E2 (PGE2) production-inhibiting rate ratio of prostaglandin induced by LPS of less than 20% based on the vehicle group, at the time of administering the effective amount of a drug to a thrombus model induced with iron chloride from the guinea pig in which clopidogrel is used concomitantly. "Illustratively, Compound A is included for example.

The "compound having an inhibition ratio of B2 production of thromboxane induced by aggregation of 70% or more based on the vehicle group and also having a ratio of inhibition of production of E2 (PG E2) of prostaglandin I induced by LPS less than 20% based on the vehicle group, at the time of administering the effective amount of a drug to a model of thrombus induced by guinea pig iron chloride in which clopidogrel is used concomitantly "means a compound that has an inhibiting ratio of thromboxane B2 production induced by aggregation of 70% or more based on the vehicle group and also having an inhibition ratio of prostaglandin E2 (PGE2) production inhibition induced by LPS of less than 20% based in the vehicle group, calculated by the method described in Example 3 of this application.

As the "agent for preventing and / or treating vascular diseases, characterized in that a selective inhibitor COX-1 or a pharmaceutically acceptable salt thereof is combined with clopidogrel or a pharmaceutically acceptable salt thereof" of the present invention, includes a pharmaceutical composition (mixed preparation) for preventing and / or treating vascular diseases, comprising an effective amount of a selective COX-1 inhibitor or a pharmaceutically acceptable salt thereof and an effective amount of clopidogrel or a pharmaceutically acceptable salt thereof, and a kit containing two kinds of preparations, particularly, as a first formulation, an agent for preventing and / or treating vascular diseases, comprises a selective COX-1 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient and, as a second formulation, an agent for preventing and / or treating vascular diseases, comprises clopidogrel or a pharmaceutically acceptable salt of the same as active ingredient. In this case, the two classes of preparations are administered simultaneously or separately through the same or different route of administration.

The "kit containing two kinds of preparations" mentioned above contains two kinds of formulations containing respective active ingredients in such a combination that can be used in the combination use therapy of these active ingredients, it is exemplified that a packaged product that can contain , as occasion demands, an additional formulation and a display member, such as a placebo preparation and the like, that facilitate administration in response to the respective administration periods. Also, "simultaneously" means that the first preparation and second preparation are administered at same time through the same route of administration, and "separately" means that the first preparation and second preparation are administered through the same or different route of administration in the same or different frequency of administration or administration interval. . Preferably, taking bioavailability, stability and the like of respective formulations under consideration, these are administered simultaneously or separately under conditions of administration such as formulation prescription, route of administration or frequency of administration and the like suitable for the respective formulations.

Compound A and / or a pharmaceutically acceptable salt thereof can be obtained easily by the production methods described in Patent Reference 1 or modified production methods thereof.

Clopidogrel or a pharmaceutically acceptable salt thereof can be obtained easily by the production methods described in US Pat. 4,529, 596 or North American Patent N o. 4,847,265 or modified production methods thereof.

The compound having an inhibiting ratio of thromboxane B2 production induced by 70% aggregation or based more on the vehicle group and also having an inhibitory ratio of prostaglandin E2 (PGE2) production induced by LPS of less than 20 % based on vehicle group, at the moment of administering the effective amount of a drug to a model of guinea pig iron chloride induced thrombosis in which the concomitant clopidogrel is used, or a pharmaceutically acceptable salt thereof, can be obtained easily by evaluating the compounds obtainable by the modalities of conventional technology in the presentation of this application, by the method of Example 3.

Suitable salts of the selective inhibitor COX-1 are generally used non-toxic salts that are acceptable as medicines, for example, metal salts such as alkali metal salts (eg, sodium salt, potassium salt and the like) or alkaline salts Metals are alkaline non-terrestrial (eg, calcium salt, magnesium salt and the like), ammonium salt, salts of organic bases (eg, trimethylammonium salt, triethylammonium salt, pi-ridinium salt, salt of picoline, dicyclohexylammonium salt and the like), salts of the organic acid (for example, acetate, maleate, tartarate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate and the like), salts of the inorganic acid (for example, hydrochloride, bromhyd , sulfate, phosphate and the like), salts with amino acids (eg, arginine, aspartic acid, glutamic acid and the like), and the like are exemplified. Suitable salts of clopidogrel are generally used non-toxic salts which are acceptable as medicines, for example, salts of organic acid (eg, acetate, malonate, tartarate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate and the like), salts of the inorganic acid (e.g., hydrochloride, hydrobromide, sulfate, phosphate and the like), amino acid salts (e.g., alginate, aspartate, glutamate and the like), and the like are exemplified. Particularly preferred is sulfate.

The selective inhibitor COX-1 and clopidogrel or pharmaceutically acceptable salts thereof can also form hydrates or various pharmaceutically acceptable solvates. These hydrates and solvates are also included in the present invention.

The pharmaceutical composition for preventing and / or treating vascular diseases, characterized in that the selective inhibitor COX-1 or a pharmaceutically acceptable salt thereof is combined with clopidogrel or a pharmaceutically acceptable salt thereof in the present invention, can be produced by preparing as a mixed preparation or separate preparations of an effective amount of a COX-1 selective inhibitor or a pharmaceutically acceptable salt thereof and an effective amount of clopidogrel or a pharmaceutically acceptable salt thereof, by a method generally used using the medicinal carrier, filler and the like which are generally used in the field. These pharmaceutical preparations can be prepared by a method generally used using the medicinal carrier, filler and the like which are generally used in the field. The administration can be any form of oral administration by tablets, pills, capsules, granules, powders, solutions and the like, or administration by parenteral, intra-articular injections, intravenous, intramuscular and similar, suppositories, eye drops, ointments for the eyes, percutaneous solutions, ointments, percutaneous patches, transmucosal solutions, transmucosal patches, inhalations and the like.

As the solid composition for oral administration by the present invention, tablets, powders, granules and the like are used. In such a solid composition, one or two or more active ingredients are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone and / or magnesium aluminometasilicate, and the like. According to the conventional process, the composition may contain additive agents with the exception of the inert diluent, for example, lubricants such as magnesium stearate and the like, disintegrating agents such as calcium cellulose glycolate and the like, stabilizing or solubilizing agents. Although occasion requires, the tablets or pills may be covered with a sugar coating or a film of gastric or enteric substance, such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, and the like.

The liquid composition for oral administration includes emulsions, solutions, suspensions, syrups or the pharmaceutically acceptable and similar excipients and contains a generally used inert diluent such as purified water or ethanol. In addition to the inert diluent, the liquid composition may contain auxiliaries such as solubilizing agents, wetting agents or suspending agents and the like, sweeteners, flavors, aromatics and antiseptics.

Injections for parenteral administration include aqueous or non-aqueous aseptic solutions, suspensions or emulsions. As the aqueous solutions or suspensions, for example, distilled water for injection or physiological saline is included. As non-aqueous solutions or suspensions, for example, vegetable oil such as propylene glycol, polyethylene glycol or olive oil or the like, alcohols such as ethanol or the like, polysorbate 80 (official name) and the like. Such a composition may additionally contain a tonicity agent, an antiseptic, a wetting agent, an emulsifying agent, a dispersing agent, a stabilizing agent or a solubility assisting agent. These are sterilized by filtration through a filter that retains bacteria, a mixture of a germicide or irradiation. Alternatively, they can be used first by making sterile solid compositions and dissolving or suspending them in sterile water or a sterile solvent for injection before use.

Transmucosal preparations such as transnasal agents and the like are used in a liquid or semi-liquid form and can be produced according to a conventionally known method. For example, agents that adjust the conventionally known pH, antiseptics, thickeners are added and filled and optionally form in a liquid or semi-solid form. The transnasal agents are administered using a general sprayer, a nasal drop container, a tube, a nasal cavity insertion tool or the like. 1) The agent containing the selective inhibitor COX-1 or a pharmaceutically acceptable salt thereof as an active ingredient or 2) the agent containing the selective inhibitor COX-1 or a pharmaceutically acceptable salt thereof and clopidogrel or a pharmaceutically acceptable salt thereof as active ingredients, both to be used in the present invention, are administered to patients having vascular diseases, and adequate daily dose 1) the selective inhibitor COX-1 or a pharmaceutically acceptable salt thereof or 2) the selective inhibitor COX-1 or a pharmaceutically acceptable salt thereof and clopidogrel or a pharmaceutically acceptable salt thereof is generally from about 0.001 to 1 00 mg / kg per body weight in the case of oral administration, which is administered once a day or dividing it into 2 to 4 servings. In the case of intravenous administration, the daily dose is approximately 0.0001 to 10 mg / kg per body weight is adequate and administered once a day or dividing it into two or more portions. Furthermore, in the case of transmucosal agents, from about 0.001 to 1000 mg / kg per body weight are administered once a day or divided into two or more portions. The dose is optionally determined in response to individual cases by taking the symptoms, ages, sexes and similar in consideration.

EXAMPLES The subject of the following Examples is described in the present invention in a further illustrative manner, and the present invention is not limited to the following Examples. Although the present invention is sufficiently described by the Examples, it can be understood by those skilled in the art that there will be various alterations and modifications. Thus, such alterations and modifications are included in the present invention without departing from the scope of the present invention.

Example 1 (Experiment) The verification of the antithrombotic action was carried out using a model of thrombosis induced with ferric chloride in guinea pigs, partially modifying the experiment described in "Thrombosis Research" (1990, vol 60, pages 269-280). Using 0.5% of methylcellulose solutions as the vehicle, the solution of clopidogrel, suspension of aspirin and suspension of Compound A was prepared. The clopidogrel solution was orally administered 2 hours before the induction of the thrombus, and the suspension of aspirin and Suspension of Compound A was administered orally 1 hour prior to the induction of the thrombus, to male Hartley guinea pigs that had been fasted. The thrombus was induced by the following procedure. Each guinea pig was laparotomized while under pentobarbital anesthesia, and the abdominal aorta It was carefully separated from the surrounding tissues. A paraffin film was separated under the detached blood vessel and a 5 mm x 4 mm piece of filter paper installed with 10% FeCl 3 solution was placed on the surface of the blood vessel, which was protected against light. The filter paper was removed 10 minutes after it, followed by 45 minutes of placing under light. Both ends of the damaged parts of the separate blood vessel were closed with clips, and the inside thereof was cut using scissors to collect the blood vessel. Cutting to open the blood vessel so that it was vertically collected, the thrombi formed in the blood vessel were removed using a pair of forceps and dissolved in 0.5 mol / L NaOH. The protein concentration was determined using the DC protein assay kit (mfd by BIO-RAD Laboratories) and according to the protocols. Using the total protein content of the thrombi formed as the antithrombotic effect index, the statistical analysis between the respective groups was performed using the Student's t-test.

(Results) The measured results of the total protein thrombus content are shown in Fig. 1. Compared with the control (vehicle administration group) (C), clopidogrel 1 mg / kg administration group (CLO 1), Compound A 3 mg / kg of administration group (Compound A3) and aspirin 300 mg / kg of administration group (ASA 300) showed a statistically significant difference. In addition, a group in which 1 mg / kg of clopidogrel and 3 mg / kg of Compound A were administered concomitantly (Compound A3 + CLO 1) showed a statistically significant difference of the administration group of clopidogrel alone (CLO 1) and administration group only Compound A (Compound A3). On the one hand, a group in which 1 mg / kg of clopidogrel and 300 mg / kg of aspirin were administered concomitantly (ASA 300 + CLO 1) showed a significant difference of the administration group only of clopidogrel (CLO 1), but a Significant difference was not found compared to the aspirin-only administration group (ASA 300), so no distinct synergistic effect was observed. In addition, a concomitant administration group of clopidogrel and Compound A (Compound A3 + CLO 1) shows a statistically significant difference from a concomitant administration group of clopidogrel and aspirin (ASA 300 + CLO 1). That is, the significantly improved antithrombotic effect of Compound A of clopidogrel compared to that of using aspirin in the dose in which it shows antithrombotic effect equal to or greater than Compound A (100 times of Compound A) was shown. Accordingly, Compound A was shown to have the effect of improving the antithrombotic efficacy of clopidogrel, which is far from surpassing conventionally used aspirin.

Example 2 (Experiment) The examination of the influence of drugs that exerts on the Gastric mucosa was performed using normal rabbit guinea pigs. Using 0.5% of methylcellulose solutions as the vehicle, the solution of clopidogrel, suspension of aspirin and suspension of Compound A was prepared. The solution of clopidogrel, suspension of aspirin or suspension of Compound A was administered orally to the guinea pigs by means of a tube. Hartley male who have undergone fasting. With respect to the dose of each drug in the case of a single drug evaluation, aspirin was administered at its pharmacologically effective dose, 300 mg / kg, and Compound A or clopidogrel at 100 mg / kg which is a dose of approximately 30 mg / kg. times greater than its pharmacologically effective dose. Also, in the evaluation at the time of the concomitant administration of clopidogrel with aspirin or Compound A, in addition to 3 mg / kg of clopidogrel, 300 mg / kg of aspirin were administered simultaneously in the group of concomitant use of aspirin, and 1 00 mg / kg of Compound A in the group of concomitant use of Compound A. After 3 hours of administration, each guinea pig was sacrificed by deep anesthesia with carbon dioxide, and the stomach was rapidly removed. The part of the esophagus of the extracted stomach was ligated, 1 5 ml of 4% neutral buffered formalin solution was injected from the pyloric part, and then light fixation was performed by immersing in the same solution for approximately 1 hour after ligating the part of the pylorus. Afterwards, the stomach was cut open along the greater curvature of the stomach, and the length (mm) of the gastric mucosal lesion it was measured using a stereoscopic microscope. Statistical analysis between the respective groups was performed using the Wilcoxon thick-sum test.

(Results) The measured results of the gastric mucosal lesion are shown in Fig. 2 and Fig. 3. Gastric mucosal damage was clearly formed in the aspirin administration group (ASA) 300 mg / kg. On the one hand, a clear action for the gastric mucosa can not be confirmed in the administration groups of Compound A (Compound A) and clopidogrel (CLO) 100 mg / kg. Gastric mucosal damage was also clearly induced by aspirin 300 mg / kg in the case of concomitant administration of clopidogrel 3 mg / kg. As for aspirin, the trend showed that gastric mucosal damage at the time of its concomitant administration with clopidogrel became worse than the gastric mucosal damage that formed when aspirin was used alone. On the one hand, a clear action for the gastric mucosa can not be confirmed in the administration group for concomitant use of Compound A (Compound A) 100 mg / kg and 3 mg / kg clopidogrel.

Example 3 (Experiment) The test on the selectivity of the inhibitory effect on Cyclooxygenase (COX) -1 / 2 was performed based on, as indices, the inhibition of production (COX-1 inhibition) of thromboxane B2 induced by coagulation (TXB2) and the inhibition of production of Prostaglandin E2 induced by LPS (PGE2) using guinea pig whole blood. Like the vehicle, 0.5% of methylcellulose solutions were used. By dissolving clopidogrel and suspending aspirin and Compound A therein, clopidogrel was administered orally 2 hours before the blood collection, and aspirin and Compound A 1 hour before the same, to male Hartley's rabbit guinea pigs that had been submitted. to fasting (administered drug groups). On the one hand, as the vehicle administration group, clopidogrel was administered orally 2 hours before the blood collection, and the vehicle 1 hour before the same. Each guinea pig was laparotomized while under ether anesthesia, 4 ml of blood was collected from the abdominal aorta, and 1 ml of it was placed in a tube adding an anticoagulant and allowed to stand and then 3 ml of it are placed in a tube loaded with 300 μ? of sodium citrate, followed by the inclination of the mixture. Whole blood added with an anticoagulant is incubated at 37 ° C for 1 hour and then indomethacin was added to a final concentration of 10 μm. , separated by centrifugation at 1 5000 rpm and at 4 ° C to collect the serum. The concentration of TXB2 in the serum was measured using a TXB2 EIA kit (mfd by Cayman Chemicals). The whole blood added with sodium citrate was mixed with LPS at a final concentration of 1 00 g / ml, incubated at 37 ° C for 24 hours, mixed with indomethacin at a final concentration of 1.0 μg. and then centrifuged at 1 5000 rpm and at 4 ° C to collect the plasma. A portion of 1 00 μ? of the plasma collected was mixed with 400 μ? of methanol and centrifuged at 1 5000 rpm and at 4 ° C, and then the whole volume of the supernatant was placed in a glass tube and evaporated to dryness using an evaporator. Adding 1 00 μ? of E IA buffer, the dried residue in the glass tube was completely dissolved. The concentration of PG E2 in the buffer was measured using a PGE2 E IA kit (mfd by Cayman Chemicals). The inhibitory rate of each of the concentration of TXB2 and concentration of PGE2 relative to the vehicle group was calculated using a calculation formula [1 00 - (concentration of drug administration group / concentration of solvent administration) x 100 (%)], and the significant difference of the vehicle segment was tested using the Student's t-test.

(Results) The results of inhibition of coagulation-induced production of TXB2 are shown in Fig. 4. Under concomitant use with 1 mg / kg of clopidogrel, both of 3 mg / kg of Compound A (Compound A) and 300 mg / kg of aspirin (ASA) showed statistically significant inhibitory effects on TXB2 production induced by coagulation compared to the vehicle administration group (C), and the inhibitory rates were 82.1% and 1 00.0%, respectively. The results of the inhibition of production of PG E2 induced by LPS are shown in Fig. 5. The significant inhibitory effect on the production of PG E2 compared to the vehicle administration group is not It was confirmed by the concomitant administration of 1 mg / kg of clopidogrel and 3 mg / kg of Compound A. On the one hand, the inhibition of significant PG E2 production could be confi rmed in comparison with the solvent administration group, when administered concomitantly 1 mg / kg of clopidogrel and 300 mg / kg of aspirin. Inhibitory rates were 0.1% and 90.4%, respectively.

Industrial Application The pharmaceutical composition of the present invention is provided by being useful as a pharmaceutical composition for preventing and / or treating vascular diseases. In addition, the pharmaceutical composition of the present invention is provided, being particularly useful as a pharmaceutical composition for preventing and / or treating aforementioned diseases, in which gastrointestinal disorders and similar side effects were reduced. In addition, the pharmaceutical composition of the present invention is provided being particularly useful as a pharmaceutical composition for preventing and / or treating arterial thrombosis, ischemic heart disease [eg, angina pectoris (eg, stable angina pectoris, angina pectoris) unstable including impending infarction, and the like), myocardial infarction (e.g., acute myocardial infarction and the like), coronary thrombosis and the like], ischemic cerebral disease [e.g., cerebral infarction (e.g., acute cerebral thrombosis and the like), cerebral thrombosis (for example, cerebral embolism and similar), transient cerebral ischemia (eg, transient ischemic attack and the like) and the like], pulmonary embolism, peripheral circulation disorder [eg, thromboangiitis obliterans (ie Buerger's disease), Raynaud's disease and the like], restenosis and reocclusion [eg restenosis and / or reocclusion after percutaneous transluminal coronary angioplasty (PTCA for its acronym in English), restenosis and reocclusion after the administration of a thrombolytic agent (eg, plasminogen tissue activating factor ( tPA for its sigla in English) or similar)] or essential thrombocytosis.

Claims

RE IVI N D ICAC IO N S

1 . An agent for preventing and / or treating vascular diseases, characterized in that a selective COX-1 inhibitor or a pharmaceutically acceptable salt thereof is combined with clopidogrel or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition, comprising 1) a selective COX-1 inhibitor or a pharmaceutically acceptable salt thereof and 2) clopidogrel or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition described in claim 2, wherein the selective initiator COX-1 is 3-methoxy-1,5-bis (4-methoxyphenyl) -1H-1, 2,4-triazole or a pharmaceutically acceptable salt. of the same.

4. A pharmaceutical composition for preventing and / or treating vascular diseases, comprising 1) a selective COX-1 inhibitor or a pharmaceutically acceptable salt thereof and 2) clopidogrel or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition described in claim 4, wherein the selective inhibitor COX-1 is 3-methoxy-1,5-bis (4-methoxyphenyl) -1 H-, 2,4-triazole or a pharmaceutically acceptable salt thereof.

6. Use of a selective COX-1 inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing and / or treating vascular diseases in combination with clopidogrel or a pharmaceutically acceptable salt thereof.

7. The use described in claim 6, wherein the selective inhibitor COX-1 is 3-methoxy-1,5-bis (4-methoxyphenyl) -1 H-1, 2,4-triazole or a pharmaceutically acceptable salt thereof.

8. A method for preventing and / or treating vascular diseases, comprising administering 1) an effective amount of clopidogrel or a pharmaceutically acceptable salt thereof and 2) an effective amount of a COX-1 selective inhibitor or a pharmaceutically acceptable salt thereof to the human or animal previously mentioned.

9. The method described in claim 8, wherein the selective inhibitor COX-1 is 3-methoxy-1,5-bis (4-methoxyphenyl) -1 H-1, 2,4-triazole or a pharmaceutically acceptable salt of the same. 1 0. A pharmaceutical composition for preventing and / or treating vascular diseases, comprising 1) a formulation comprising a selective COX-1 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient and 2) a package insert indicating that the formulation it is used in combination with a formulation containing clopidogrel or a pharmaceutically acceptable salt thereof as an active ingredient. SUMMARY An excellent pharmaceutical composition for preventing and / or treating vascular diseases is provided. It is useful to provide a pharmaceutical composition for preventing and / or treating vascular diseases, comprising 1) a selective inhibitor COX-1 and 2) clopidogrel or a pharmaceutically acceptable salt thereof. The present invention is provided which is useful as an excellent pharmaceutical composition for preventing and / or treating vascular diseases and is particularly useful as a pharmaceutical composition for preventing and / or treating arterial thrombosis, ischemic cardiac disease, ischemic cerebral disease, pulmonary embolism, of peripheral circulation, restenosis and reocclusion, essential thrombocytosis and so on.